This project will help to clarify the pathogenesis of Alport syndrome and investigate a new strategy for treatment. The first aim will be to study how type IV collagen folds around natural sequence interruptions, which exist benignly in the normal collagen sequence. Recombinant collagen will be used to study the effect of interruptions on folding kinetics by circular dichroism, trypsin susceptibility, fluorescence, and electron microscopy. A subset of natural interruptions is similar to the sequences created by glycine missense mutations that cause Alport syndrome. The second aim will be to examine the differences between these interruptions and mutations in sequence, structure, and folding to provide insight into defective folding around mutations. Peptide and recombinant systems will be employed to obtain structural and kinetic information. The third aim will be to test small molecule chaperones to determine whether they can correct folding defects caused by missense mutations.